Cardiometabolic Lipid Disorders
Cardiometabolic lipid disorders are complex, with a multitude of risk factors. There is a growing body of evidence through genomics and epidemiological studies supporting the need for new therapies targeting the protein and lipid risk factors associated with these cardiometabolic lipid disorders.
Lipid and lipoprotein risk factors, including LDL-C, triglycerides, apolipoprotein C-III (ApoC-III) and Lp(a), are related to many diseases, both rare and relatively common. They result in a variety of unmet medical needs, varying in severity, and manifesting in a range of clinical presentations including pancreatitis, diabetes, liver disease, and multiple forms of cardiovascular disease.
Our current disease areas of focus include:
FCS is a Life-threatening Disease with Multiple Severe Daily and Chronic Manifestations
Familial chylomicronemia syndrome (FCS) is a rare, genetic lipid disorder characterized by the build-up of chylomicrons (chylomicronemia), a large lipoprotein particle that transport dietary fat and cholesterol in the body. Because chylomicrons are rich in triglycerides, people with FCS have extremely high levels of triglycerides, often reaching 10 to 20 times the normal level. People with FCS cannot break down chylomicrons, so their blood can appear milky in color (lipemic). There are approximately 3,000 to 5,000 patients with FCS worldwide.
The extremely high level of triglycerides in people with FCS result in multiple, frequently occurring manifestations that interfere with activities of daily living, and they live with the risk of severe recurrent abdominal pain and potentially life-threatening pancreatic attacks as well as potential long-term complications from pancreatic damage.
Severe, lifelong dietary restrictions are imposed on patients with FCS to help manage complications of the disease, but even when adhering to a strict diet, triglycerides often remain well outside the normal range.
As part of our ongoing commitment to better understanding this rare disease, Akcea designed and conducted the IN-FOCUS study, a patient survey focusing on elements of the experience of people living with FCS, including physical, psychosocial, cognitive, and economic burdens that this disease places on patients’ lives. The results of this survey identified a number of disease burdens that have not been previously captured in literature, including emotional and cognitive daily manifestations that extend beyond the physical manifestations of the disease. Symptoms identified as part of the IN-FOCUS study include:
- Physical: Nausea, vomiting, abdominal pain multiple times a week, and severe pancreatic pain on a monthly basis
- Cognitive: Memory loss, confusion, difficulty concentrating, and substantial fatigue that interfere with their professional, personal and social activities
Familial partial lipodystrophy (FPL)
Familial partial lipodystrophy (FPL) is a rare lipid disorder characterized by abnormal fat distribution across the body and a range of metabolic abnormalities, including severe insulin resistance, dyslipidemia and hypertriglyceridemia, hepatic steatosis and, in affected women, features of hyperandrogenism.
People with FPL are unable to store fat or triglycerides in normal fat stores so excess triglycerides are stored in the liver and muscle and accumulate at high levels in the bloodstream – often reaching more than five times the normal level. Additionally, because those with FPL cannot store excess triglycerides, their plasma triglyceride levels are extremely elevated after meals. These triglycerides deposit in organs other than normal fat tissue, known as ectopic fat. Ectopic fat accumulation may affect many organs, but primarily leads to health issues in the liver, pancreas and skeletal muscles.
People with FPL are at increased risk of life-threatening pancreatitis, accumulation of harmful fat in the liver (hepatic steatosis) and nonalcoholic steatohepatitis (NASH), enlarged livers, polycystic ovarian syndrome, and premature cardiovascular disease.
Cardiovascular disease caused by hyperlipoproteinemia(a)
Elevated lipoprotein(a), or Lp(a), is recognized as an independent, genetic cause of coronary artery disease, heart attack, stroke and peripheral arterial disease.
People with elevated levels of ANGPTL3 have high LDL C and triglyceride levels. Studies show this elevation is associated with an increased risk of premature heart attacks, increased arterial wall thickness and multiple metabolic disorders, such as insulin resistance. In contrast, people with lower levels of ANGPTL3 have lower LDL C and triglyceride levels and thus lower risk of heart attacks and multiple metabolic disorders.
Non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD)
Patients with fatty liver disorders, including non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD), may benefit from reduced ANGPTL3 levels. Fatty liver disease is a growing problem globally due to increasing metabolic disease. Patients with NASH and NAFLD often have associated dyslipidemia. As a result, most NASH patients die from cardiovascular disease. Reducing ANGPTL3 has the potential to improve both cardiovascular risk and liver fat in these patients.
Cardiovascular disease driven by high triglycerides
There is a broad population of patients who are at risk for cardiometabolic disease due to their elevated triglyceride levels.